TRIM25 promotes antiviral innate immune response by stabilizing IRF7 and its nuclear translocation

Most avian species, including those in the orders <i>Galliformes</i> and <i>Anseriformes</i>, lack IRF3; consequently, IRF7 plays a pivotal and more comprehensive role in regulating innate immunity against viral infections. However, the activation and regulation by IRF7 in avian remain insufficiently characterized. In this study, we identify the E3 ubiquitin ligase duck TRIM25 as a positive regulator of IRF7. Functioning as an E3 ligase, TRIM25 stabilizes IRF7 expression and promotes its nuclear translocation through K27-linked polyubiquitination, thereby enhancing IFN-I production. Additionally, TRIM25 stabilizes IRF7 independently of its E3 ligase activity by suppressing SOCS1-mediated degradation. Activation of TRIM25 <i>in vivo</i> in ducks exhibits significant efficacy in antagonizing RNA virus infection. Collectively, our findings demonstrate that TRIM25 functions as a positive regulator, promoting IRF7-dependent signaling pathways to combat RNA viruses. This establishes TRIM25 as a crucial regulatory factor and potential target within the antiviral response.